INDICATIONS

Guanfacine hydrochloride (guanfacine) tablets are indicated in the management of hypertension.
Guanfacine may be given alone or in combination with other antihypertensive
agents, especially thiazide-type diuretics.

DOSAGE AND ADMINISTRATION

The recommended initial dose of guanfacine (as the hydrochloride) when given
alone or in combination with another antihypertensive drug is 1 mg daily given
at bedtime to minimize somnolence. If after 3 to 4 weeks of therapy, 1 mg does
not give a satisfactory result, a dose of 2 mg may be given, although most of
the effect of guanfacine is seen at 1 mg (see CLINICAL
PHARMACOLOGY). Higher daily doses have been used, but adverse reactions
increase significantly with doses above 3 mg/day.

The frequency of rebound hypertension is low, but it can occur. When rebound
occurs, it does so after 2-4 days, which is delayed compared with clonidine
hydrochloride. This is consistent with the longer half-life of guanfacine. In
most cases, after abrupt withdrawal of guanfacine, blood pressure returns to
pretreatment levels slowly (within 2-4 days) without ill effects.

HOW SUPPLIED

Guanfacine hydrochloride is available in 2 tablet strengths of guanfacine (as
the hydrochloride) as follows:

Guanfacine Hydrochloride (guanfacine) Tablets 1 mg, are pink, round tablets, debossed with
WATSON 444 and are available in bottles of 100.

Guanfacine Hydrochloride (guanfacine) Tablets 2 mg, are peach, round tablets, debossed with
WATSON 453 and are available in bottles of 100.

SIDE EFFECTS

Adverse reactions noted with guanfacine are similar to those of other drugs
of the central a2 adrenoreceptor agonist class: dry mouth, sedation (somnolence),
weakness (asthenia), dizziness, constipation, and impotence. While the reactions
are common, most are mild and tend to disappear on continued dosing.

Skin rash with exfoliation has been reported in a few cases; although clear
cause and effect relationships to guanfacine could not be established, should
a rash occur, guanfacine should be discontinued and the patient monitored appropriately.

In the dose-response monotherapy study described under CLINICAL
PHARMACOLOGY, the frequency of the most commonly observed adverse reactions
showed a dose relationship from 0.5 to 3 mg as follows:

Adverse Reaction

Placebo

0.5 mg

1 mg

2 mg

3 mg

n=59

n=60

n=61

n=60

n=59

Dry Mouth

0%

10%

10%

42%

54%

Somnolence

8%

5%

10%

13%

39%

Asthenia

0%

2%

3%

7%

3%

Dizziness

8%

12%

2%

8%

15%

Headache

8%

13%

7%

5%

3%

Impotence

0%

0%

0%

7%

3%

Constipation

0%

2%

0%

5%

15%

Fatigue

2%

2%

5%

8%

10%

The percent of patients who dropped out because of adverse reactions are shown
below for each dosage group.

Placebo

0.5 mg

1 mg

2 mg

3 mg

Percent dropouts

0%

2%

5%

13%

32%

The most common reasons for dropouts among patients who received guanfacine
were dry mouth, somnolence, dizziness, fatigue, weakness, and constipation.

In the 12-week placebo-controlled, dose-response study of guanfacine administered
with 25 mg chlorthalidone at bedtime, the frequency of the most commonly observed
adverse reactions showed a clear dose relationship from 0.5 to 3 mg as follows:

Adverse Reaction

Placebo

0.5 mg

1 mg

2 mg

3 mg

n=73

n=72

n=72

n=72

n=72

Dry mouth

5 (7%)

4 (5%)

6 (8%)

8 (11%)

20 (28%)

Somnolence

1 (1%)

3 (4%)

0 (0%)

1 (1%)

10 (14%)

Asthenia

0 (0%)

2 (3%)

0 (0%)

2 (2%)

7 (10%)

Dizziness

2 (2%)

1 (1%)

3 (4%)

6 (8%)

3 (4%)

Headache

3 (4%)

4 (3%)

3 (4%)

1 (1%)

2 (2%)

Impotence

1 (1%)

1 (0%)

0 (0%)

1 (1%)

3 (4%)

Constipation

0 (0%)

0 (0%)

0 (0%)

1 (1%)

1 (1%)

Fatigue

3 (3%)

2 (3%)

2 (3%)

5 (6%)

3 (4%)

There were 41 premature terminations because of adverse reactions in this study.
The percent of patients who dropped out and the dose at which the dropout occurred
were as follows:

In a second 12-week placebo-controlled combination therapy study in which the
dose could be adjusted upward to 3 mg per day in 1-mg increments at 3-week intervals,
i.e., a setting more similar to ordinary clinical use, the most commonly recorded
reactions were: dry mouth, 47%; constipation, 16%; fatigue, 12%; somnolence,
10%; asthenia, 6%; dizziness, 6%; headache, 4%; and insomnia, 4%.

Postmarketing Experience: An open-label postmarketing study involving 21,718
patients was conducted to assess the safety of guanfacine (as the hydrochloride)
1 mg/day given at bedtime for 28 days. Guanfacine was administered with or without
other antihypertensive agents. Adverse events reported in the postmarketing
study at an incidence greater than 1% included dry mouth, dizziness, somnolence,
fatigue, headache, and nausea. The most commonly reported adverse events in
this study were the same as those observed in controlled clinical trials.

DRUG ABUSE AND DEPENDENCE

No reported abuse or dependence has been associated with the administration
of guanfacine.

Drug Interactions

DRUG INTERACTIONS

The potential for increased sedation when guanfacine is given with other CNS-depressant
drugs should be appreciated.

The administration of guanfacine concomitantly with a known microsomal enzyme
inducer (phenobarbital or phenytoin) to two patients with renal impairment reportedly
resulted in significant reductions in elimination half-life and plasma concentration.
In such cases, therefore, more frequent dosing may be required to achieve or
maintain the desired hypotensive response. Further, if guanfacine is to be discontinued
in such patients, careful tapering of the dosage may be necessary in order to
avoid rebound phenomena (see Rebound above).

Anticoagulants

Ten patients who were stabilized on oral anticoagulants were given guanfacine,
1-2 mg/day, for 4 weeks. No changes were observed in the degree of anticoagulation.

Sedation

Guanfacine, like other orally active central a2 adrenergic agonists, causes
sedation or drowsiness, especially when beginning therapy. These symptoms are
dose-related (see ADVERSE REACTIONS). When
guanfacine is used with other centrally active depressants (such as phenothiazines,
barbiturates, or benzodiazepines), the potential for additive sedative effects
should be considered.

Rebound

Abrupt cessation of therapy with orally active central a2 adrenergic agonists
may be associated with increases (from depressed on-therapy levels) in plasma
and urinary catecholamines, symptoms of "nervousness and anxiety"
and, less commonly, increases in blood pressure to levels significantly greater
than those prior to therapy.

Laboratory Tests

In clinical trials, no clinically relevant laboratory test abnormalities were
identified as causally related to drug during short-term treatment with guanfacine.

Drug/Laboratory Test Interactions

No laboratory test abnormalities related to the use of guanfacine have been
identified.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenic effect was observed in studies of 78 weeks in mice at doses
more than 150 times the maximum recommended human dose and 102 weeks in rats
at doses more than 100 times the maximum recommended human dose. In a variety
of test models, guanfacine was not mutagenic.

No adverse effects were observed in fertility studies in male and female rats.

Pregnancy Category B

Administration of guanfacine to rats at 70 times the maximum recommended human
dose and to rabbits at 20 times the maximum recommended human dose resulted
in no evidence of harm to the fetus. Higher doses (100 and 200 times the maximum
recommended human dose in rabbits and rats respectively) were associated with
reduced fetal survival and maternal toxicity. Rat experiments have shown that
guanfacine crosses the placenta.

There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response,
this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Guanfacine is not recommended in the treatment of acute hypertension associated
with toxemia of pregnancy. There is no information available on the effects
of guanfacine on the course of labor and delivery.

Nursing Mothers

It is not known whether guanfacine is excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised when guanfacine
hydrochloride is administered to a nursing woman. Experiments with rats have
shown that guanfacine is excreted in the milk.

Pediatric Use

Safety and effectiveness in pediatric patients under 12 years of age have not
been demonstrated. Therefore, the use of guanfacine in this age group is not
recommended. There have been spontaneous postmarketing reports of mania and
aggressive behavioral changes in pediatric patients with attention-deficit hyperactivity
disorder (ADHD) receiving guanfacine. The reported cases were from a single
center. All patients had medical or family risk factors for bipolar disorder.
All patients recovered upon discontinuation of guanfacine HCl.

Geriatric Use

Clinical studies of guanfacine did not include sufficient numbers of subjects
aged 65 and over to determine whether they responded differently from younger
subjects. Other reported clinical experience has not identified differences
in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal or cardiac function, and of concomitant disease
or other drug therapy (see CLINICAL PHARMACOLOGY,
Pharmacokinetics).

Overdosage & Contraindications

OVERDOSE

A 25-year-old female intentionally ingested 60 mg. She presented with severe
drowsiness and bradycardia of 45 beats/minute. Gastriclavage was performed
and an infusion of isoproterenol (0.8 mg in 12 hours) was administered. She
recovered quickly and without sequelae.

A 28-year-old female who ingested 30-40 mg developed only lethargy, was treated
with activated charcoal and a cathartic, was monitored for 24 hours, and was
discharged in good health.

A 2-year-old male weighing 12 kg, who ingested up to 4 mg of guanfacine, developed
lethargy. Gastric lavage (followed by activated charcoal and sorbitol slurry
via NG tube) removed some tablet fragments within 2 hours after ingestion, and
vital signs were normal.

During 24-hours observation in ICU, systolic pressure was 58 and heart rate
70 at 16 hours postingestion. No intervention was required, and child was discharged
fully recovered the next day.

Treatment of Overdosage: Gastric lavage and supportive therapy as appropriate.
Guanfacine is not dialyzable in clinically significant amounts (2.4%).

CONTRAINDICATIONS

Guanfacine hydrochloride (guanfacine) tablets are contraindicated in patients with known
hypersensitivity to the drug.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Guanfacine hydrochloride (guanfacine) is an orally active antihypertensive agent whose principal
mechanism of action appears to be stimulation of central a2-adrenergic receptors.
By stimulating these receptors, guanfacine reduces sympathetic nerve impulses
from the vasomotor center to the heart and blood vessels. This results in a
decrease in peripheralvascularresistance and a reduction in heart rate.

The dose-response relationship for blood pressure and adverse effects of guanfacine
given once a day as monotherapy has been evaluated in patients with mild to
moderate hypertension. In this study patients were randomized to placebo or
to 0.5 mg, 1 mg, 2 mg, 3 mg, or 5 mg of guanfacine. Results are shown in the
following table. A useful effect was not observed overall until doses of 2 mg
were reached, although responses in white patients were seen at 1 mg; 24 hour
effectiveness of 1 mg to 3 mg doses was documented using 24 hour ambulatory
monitoring. While the 5 mg dose added an increment of effectiveness, it caused
an unacceptable increase in adverse reactions.

Controlled clinical trials in patients with mild to moderate hypertension who
were receiving a thiazide-type diuretic have defined the dose-response relationship
for blood pressure response and adverse reactions of guanfacine given at bedtime
and have shown that the blood pressure response to guanfacine can persist for
24 hours after a single dose. In the 12-week placebo-controlled dose-response
study, patients were randomized to placebo or to doses of 0.5, 1, 2, and 3 mg
of guanfacine, in addition to 25 mg chlorthalidone, each given at bedtime. The
observed mean changes from baseline, tabulated below, indicate the similarity
of response for placebo and the 0.5 mg dose. Doses of 1, 2, and 3 mg resulted
in decreased blood pressure in the sitting position with no real differences
among the three doses. In the standing position there was some increase in response
with dose.

Mean Decreases (mm Hg) in Seated and Standing Blood Pressure
for Patients Treated with Guanfacine in Combination with Chlorthalidone

Placebo

0.5 mg

1 mg

2 mg

3 mg

Mean Change

n=

63

63

64

58

59

S/D* Seated

-5/-7

-5/-6

-14/-13

-12/-13

-16/-13

S/D* Standing

-3/-5

-5/-4

-11/-9

-9/-10

-15/-12

*S/D = Systolic/diastolic blood pressure

While most of the effectiveness of guanfacine in combination (and as monotherapy
in white patients) was present at 1 mg, adverse reactions at this dose were
not clearly distinguishable from those associated with placebo. Adverse reactions
were clearly present at 2 and 3 mg (see ADVERSE REACTIONS).

In a second 12-week placebo-controlled study 1, 2, or 3 mg of guanfacine hydrochloride (guanfacine)
administered with 25 mg chlorthalidone once daily, a significant decrease in
blood pressure was maintained for a full 24 hours after dosing. While there
was no significant difference between the 12 and 24 hour blood pressure readings,
the fall in blood pressure at 24 hours was numerically smaller, suggesting possible
escape of blood pressure in some patients and the need for individualization
of therapy.

In a double-blind, randomized trial, either guanfacine or clonidine was given
at recommended doses with 25 mg chlorthalidone for 24 weeks and then abruptly
discontinued. Results showed equal degrees of blood pressure reduction with
the two drugs and there was no tendency for blood pressures to increase despite
maintenance of the same daily dose of the two drugs. Sign and symptoms of rebound
phenomena were infrequent upon discontinuation of either drug. Abrupt withdrawal
of clonidine produced a rapid return of diastolic and especially, systolic blood
pressure to approximately pretreatment levels, with occasional values significantly
greater than baseline, whereas guanfacine withdrawal produced a more gradual
increase to pretreatment levels, but also with occasional values significantly
greater than baseline.

Pharmacodynamics

Hemodynamic studies in man showed that the decrease in blood pressure observed
after single-dose or long-term oral treatment with guanfacine was accompanied
by a significant decrease in peripheral resistance and a slight reduction in
heart rate (5 beats/min). Cardiac output under conditions of rest or exercise
was not altered by guanfacine.

Guanfacine lowered elevated plasma renin activity and plasma catecholamine
levels in hypertensive patients, but this does not correlate with individual
blood-pressure responses.

Growth hormone secretion was stimulated with single oral doses of 2 and 4 mg
of guanfacine. Long-term use of guanfacine had no effect on growth hormone levels.

Guanfacine had no effect on plasma aldosterone. A slight but insignificant
decrease in plasma volume occurred after one month of guanfacine therapy. There
were no changes in mean body weight or electrolytes.

Pharmacokinetics

Relative to an intravenous dose of 3 mg, the absolute oral bioavailability
of guanfacine is about 80%. Peak plasma concentrations occur from 1 to 4 hours
with an average of 2.6 hours after single oral doses or at steady state.

The area under the concentration-time curve (AUC) increases linearly with the
dose.

In individuals with normal renal function, the average elimination half-life
is approximately 17 hr (range 10-30 hr). Younger patients tend to have shorter
elimination half-lives (13-14 hr) while older patients tend to have half-lives
at the upper end of the range. Steady state blood levels were attained within
4 days in most subjects.

In individuals with normal renal function, guanfacine and its metabolites are
excreted primarily in the urine. Approximately 50% (40-75%) of the dose is eliminated
in the urine as unchanged drug; the remainder is eliminated mostly as conjugates
of metabolites produced by oxidative metabolism of the aromatic ring.

The guanfacine-to-creatinine clearance ratio is greater than 1, which would
suggest that tubular secretion of drug occurs.

The drug is approximately 70% bound to plasma proteins, independent of drug
concentration.

The whole body volume of distribution is high (a mean of 6.3 L/kg), which suggests
a high distribution of drug to the tissues.

The clearance of guanfacine in patients with varying degrees of renal insufficiency
is reduced, but plasma levels of drug are only slightly increased compared to
patients with normal renal function. When prescribing for patients with renal
impairment, the low end of the dosing range should be used. Patients on dialysis
also can be given usual doses of guanfacine hydrochloride (guanfacine) as the drug is poorly
dialyzed.

Medication Guide

PATIENT INFORMATION

Patients who receive guanfacine should be advised to exercise caution when
operating dangerous machinery or driving motor vehicles until it is determined
that they do not become drowsy or dizzy from the medication. Patients should
be warned that their tolerance for alcohol and other CNS depressants may be
diminished. Patients should be advised not to discontinue therapy abruptly.